Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation
Monday, November 11, 2013, 1:00 pm - 4:15 pm
408.04: Therapeutic interventions targeting mitochondrial dysfunction in neurodegenerative diseases
*M. BEAL; Cornell Univ. Med. Col., NEW YORK, NY
Abstract Body: There is evidence linking mitochondrial dysfunction to the pathogenesis of neurodegenerative diseases. Impaired mitophagy and mitochondrial trafficking occur Parkinson’s disease (PD), Alzheimer’s disease (AD), ALS, and Huntington’s disease (HD). A common factor in many of these diseases is impaired function of the transcriptional coactivator PGC1-alpha, which plays an essential role in both mitochondrial biogenesis, as well as expression of antioxidant enzymes and autophagy. There is an impairment of PGC1-alpha in AD, HD, and in PD. In PD an impairment of the ubiquitin E3 ligase parkin, leads to a build up of the protein PARIS which binds to the PGC1-alpha promoter and inhibits its expression, leading to degeneration of dopaminergic neurons. Small molecule antioxidants such as SS31 and SS20 are efficacious against MPTP toxicity and in a transgenic mouse model of ALS, as is XJB-5-131 in HD. We showed that pan- PPAR agonists, such as bezafibrate, increase the expression of PGC1-alpha and produce neuroprotective effects. Bezafibrate showed neuroprotective effects in a transgenic mouse models of HD, and in the P3O1S tau mutant mice. It produced a significant increase in numbers of mitochondria and a reduction in oxidative damage. Another approach is to activate sirtuins which deacetylate proteins in both the cytoplasm as well as in mitochondria, leading to expression of PGC-1alpha, chaperone proteins, and mitochondrial antioxidants such as manganese superoxide dismutase. Lastly, activation of the nrf2/ARE pathway activates neuroprotective responses including the activation of enzymes that synthesize glutathione, thioredoxins, and hemeoxygenase, as well as increasing expression a number of heat shock protein chaperones. Triterpenoids, which are potent activators of the nrf2/ARE pathways are neuroprotective in transgenic mouse models of AD, HD, and ALS. Therapeutic strategies targeting oxidative stressor which activate transcriptional pathways which can ameliorate mitochondrial dysfunction have great promise for the treatment of neurodegenerative diseases.
Lay Language Summary: Society For Neuroscience - 2013 Abstract Control/Tracking Number: 2013-S-1375-5FN Therapeutic Interventions Targeting Mitochondrial Dysfunction in Neurodegenerative Diseases Our research shows that treatment with antioxidants which target mitochondria, or activating genetic pathways which increase the production of new mitochondria and antioxidant enzymes, and which reduce inflammation are effective in transgenic and toxin models of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and ALS. There is increasing evidence that mitochondria and oxidative damage play a critical role in the pathogenesis of neurodegenerative diseases. Mitochondria are known as the power plant of the cell and are responsible for generating energy necessary for all intracellular processes. They are the site where glucose is converted into ATP, a cellular currency of energy. A secondary consequence of the production of energy is that there is leakage of electrons which react with oxygen to generate free radicals. The production of new mitochondria, as well as the expression of antioxidant enzymes which protect against damage produced by free radicals, is controlled by a transcriptional coactivator known as PGC1-alpha. PGC1-alpha also plays a role in getting rid of damaged mitochondria. The activity and levels of PGC1-alpha are impaired in Alzheimer’s disease, Huntington’s disease, and in Parkinson’s disease. In Parkinson’s disease, a genetic cause of early onset disease is due to an impairment of a normal cellular process which gets rid of damaged proteins. This leads to a build up of a protein named PARIS, which then binds to the DNA an inhibits PGC-1alpha expression, leading to degeneration of dopaminergic neurons. A number of therapeutic approaches targeting mitochondria have been developed which show efficacy in animal models of neurodegenerative diseases. One approach is using small molecule antioxidants such as SS31 and SS20 which are selectively localized to mitochondria and protect against MPTP toxicity, a compound which is used to model Parkinson’s disease, as well as in transgenic mouse models of amyotrophic lateral sclerosis (ALS). Another mitochondrial targeted antioxidant is known as XJB-5-131, and it is neuroprotective in a transgenic mouse model of Huntington’s disease (HD). One way of activating PGC1-alpha is to use a group of drugs known as PPAR agonists, some of which were initially developed for treatment of elevated blood lipids. Both bezafibrate and fenofibrate are PPAR agonists, which show neuroprotective effects in transgenic mouse models of HD, and fronto-temporal dementia. Bezafibrate increases the numbers of mitochondria, and it reduces oxidative damage in these transgenic mice. Another approach is to activate gene expression with compounds that activate nrf2/ARE signaling. Activation of nrf2/ARE increases antioxidant enzymes and protein chaperones, and it reduces the inflammatory processes caused by inducible nitric oxide synthase and cyclooxygenase 2. Compounds activating nrf2/ARE are effective in transgenic mouse models of Alzheimer’s disease, Huntington’s disease, and ALS. Therapeutic strategies targeting both mitochondria and antioxidant pathways, therefore, have great promise for the treatment of neurodegenerative diseases.
Neuroscience 2013 (43rd annual meeting of the Society for Neuroscience)Exit